Pharmaceutical composition containing 2,2-dichloro-12-(4-chlorophenyl)-dodecanoic acid

ABSTRACT

A highly stable pharmaceutical composition which comprises a mixture comprising a substance selected from the group consisting of 2,2-dichloro-12-(4-chlorophenyl)-dodecanoic acid, salts thereof, and esters thereof, and croscarmellose sodium.

TECHNICAL FIELD

The present invention relates to a highly stable pharmaceuticalcomposition comprising 2,2-dichloro-12-(4-chlorophenyl)-dodecanoic acid.

BACKGROUND ART

2,2-Dichloro-12-(4-chlorophenyl)-dodecanoic acid has valuablepharmacological properties, such as normalization of a high blood sugarlevel without a risk of hypoglycemia as well as reduction oftriglyceride, cholesterol, and fibrinogen, and thus is promising as amedicament for treatment of diabetes mellitus (Japanese PatentPublication [Kohyo] No.10-510515/1998). However, the aforementionedcompound decomposes chronologically, which leads to a decrease of acontent. Therefore, an improvement of stability in pharmaceuticalpreparations has been desired.

Examples of means to prevent unstabilization caused by moisture oroxygen include, in general, a method of application of a wax-coating topharmaceuticals or mixing of corn starch which is capable of retainingmoisture, and a method of preservation of pharmaceuticals under nitrogensubstitution. However, when a wax-coating is applied to theaforementioned compound, a problem, retardation of dissolution of theactive ingredient, may occur. When corn starch is admixed even at asufficient amount to retain moisture, another problem arises, that saidingredient may fail to achieve a satisfactory effect and deteriorateformative property at compression. The preservation method with nitrogensubstitution is also undesirable because of its poor stabilizationeffect and complicated manufacturing process. Therefore, development ofa means to improve stability of the aforementioned compound has beendesired.

DISCLOSURE OF THE INVENTION

An object of the present invention is to provide a highly stablepharmaceutical composition comprising2,2-dichloro-12-(4-chlorophenyl)-dodecanoic acid.

The inventors of the present invention made intensive research toachieve the foregoing object. As a result, the inventors found that,when 2,2-dichloro-12-(4-chlorophenyl)-dodecanoic acid and croscarmellosesodium were mixed, stability of2,2-dichloro-12-(4-chlorophenyl)-dodecanoic acid in the mixture wasimproved. The present invention was achieved on the basis of the abovefindings.

The present invention thus provides a pharmaceutical composition whichcomprises a mixture comprising a substance selected from the groupconsisting of 2,2-dichloro-12-(4-chlorophenyl)-dodecanoic acid, saltsthereof, and esters thereof, and croscarmellose sodium.

According to a preferred embodiment of the present invention, thepresent invention provides the aforementioned pharmaceutical compositionin which a mixing ratio of the substance selected from the groupconsisting of 2,2-dichloro-12-(4-chlorophenyl)-dodecanoic acid, saltsthereof, and esters thereof, and croscarmellose sodium is from 10:1 to1:20.

From another aspect, the present invention provides a stabilizer of asubstance selected from the group consisting of2,2-dichloro-12-(4-chlorophenyl)-dodecanoic acid, salts thereof, andesters thereof, which comprises croscarmellose sodium.

From further aspect, the present invention provides a method forstabilization of a substance selected from the group consisting of2,2-dichloro-12-(4-chlorophenyl)-dodecanoic acid, salts thereof, andesters thereof, which comprises the step of preparing a mixturecomprising a substance selected from the group consisting of2,2-dichloro-12-(4-chlorophenyl)-dodecanoic acid, salts thereof, andesters thereof, and croscarmellose sodium.

BEST MODE FOR CARRYING OUT THE INVENTION

The pharmaceutical composition of the present invention comprises, as anactive ingredient, a substance selected from the group consisting of2,2-dichloro-12-(4-chlorophenyl)-dodecanoic acid, salts thereof, andesters thereof. The salts include salts of alkali metals, salts ofalkaline earth metals, ammonium salt, salts of alkyl ammoniums or thelike. Examples include, sodium salt, potassium salt, magnesium salt,calcium salt, tetramethyl ammonium salt or the like. Examples of theesters include esters with C1 to C6 aliphatic alcohols which are forexample methyl ester, ethyl ester, propyl ester, butyl ester, isopropylester or the like. Among the aforementioned compounds, sodium salt of2,2-dichloro-12-(4-chlorophenyl)-dodecanoic acid is particularlypreferred.

2,2-Dichloro-12-(4-chlorophenyl)-dodecanoic acid can be prepared, forexample, by the method described in Japanese Patent Publication [Kohyo]No. 10-510515/1998. Salts and esters thereof can also be readilyprepared by those skilled in the art with an ordinary method.

Croscarmellose sodium used in the present invention is a crosslinkedpolymer of carboxymethylcellulose sodium, and is commercially availableas, for example, Ac-Di-Sol (Asahi Kasei Co., Ltd.) or the like.Croscarmellose sodium is widely used in the art as an excipient, adisintegrant, or a disintegrating adjuvant, and easily available tothose in the art.

In the mixture comprising the substance selected from the groupconsisting of 2,2-dichloro-12-(4-chlorophenyl)-dodecanoic acid, saltsthereof, and esters thereof, and croscarmellose sodium, a mixing ratioof the components is not particularly limited. For example, the ratio.ofthe aforementioned substance and croscarmellose sodium is preferablyfrom 10:1 to 1:20, and the most preferably from 2:1 to 1:15.

One or more pharmaceutical additives generally used for manufacture ofpharmaceutical preparations may be further added to the pharmaceuticalcomposition of the present invention in addition to the aforementionedingredients, if required. The examples of such pharmaceutical additivesinclude excipients, binders, disintegrants, lubricants or the like.

Examples of the excipients include lactose, saccharose, starch,microcrystalline cellulose, sucrose, mannitol, xylitol, hydrogenatedoil, light anhydrous silicic acid, dibasic calcium phosphate or thelike. An amount of the excipient may preferably be from 10 to 95% byweight, more preferably from 30 to 90% by weight, and the mostpreferably from 60 to 90% by weight based on the total weight of thecomposition.

Examples of the binder include methylcellulose, hydroxypropylcellulose,hydroxypropylmethylcellulose, pregelatinized starch,polyvinylpyrrolidone, polyvinylalcohol, gelatin, pullulan or the like.An amount of the binder may preferably be from 1 to 10% by weight, morepreferably from 2 to 8% by weight, and the most preferably from 3 to 6%by weight based on the total weight of the composition.

Examples of the disintegrant include carmellose calcium, low-substitutedhydroxypropylcellulose, corn starch, sodium carboxymethyl starch or thelike. An amount of the disintegrant may preferably be from 2 to 25% byweight, more preferably from 3 to 15% by weight, and the most preferablyfrom 4 to 10% by weight based on the total weight of the composition.

Examples of the lubricants include magnesium stearate, calcium stearate,talc or the like. An amount of the lubricants may preferably be from0.01 to 5.0% by weight, more preferably from 0.1 to 2.0% by weight, andmost preferably from 0.5 to 1.0% by weight based on the total weight ofthe composition.

When the aforementioned pharmaceutical additives are used, an amount ofthe substance selected from the group consisting of2,2-dichloro-12-(4-chlorophenyl)-dodecanoic acid, salts thereof, andesters thereof may preferably be from 0.1 to 30% by weight, morepreferably from 0.1 to 20% by weight, and the most preferably from 0.1to 10% by weight based on the total weight of the composition. When theaforementioned pharmaceutical additives are used, an amount of thecroscarmellose sodium may preferably be from 0.1 to 30% by weight, morepreferably from 0.1 to 20% by weight, and the most preferably from 0.1to 15% by weight based on the total weight of the composition.

The pharmaceutical composition of the present invention can be preparedby mixing a given amount of the substance selected from the groupconsisting of 2,2-dichloro-12-(4-chlorophenyl)-dodecanoic acid, saltsthereof, and esters thereof and croscarmellose sodium by using, forexample, a V-blender or the like. For preparation of the aforementionedmixture, pharmaceutical additives such as excipients, disintegrants,binders or the like may be added to the mixture, if necessary. After anappropriate formulation process of the mixture is applied as required,such as pulverization or granulation, the pharmaceutical compositionsuch as tablets or capsules may be prepared by suitable means availableto those skilled in the art.

For preparation of the pharmaceutical compositions, the aforementionedmixture, per se, may be used. Alternatively, tablets or capsules may bemanufactured by adding appropriate pharmaceutical additives to themixture as required and by applying ordinary procedures available tothose skilled in the art. For example, tablets can be prepared by addingpharmaceutical additives such as an excipient and a binder to theaforementioned mixture and then compressing with wet granulation (wetprocess) or direct compression (dry process). Capsules can be preparedby pulverization or granulation of aforementioned mixture andsubsequently filling the resulting product in gelatin capsules, HPMC(hydroxypropylmethylcellulose) capsules or the like. Forms of thepharmaceutical composition of the present invention are not particularlylimited so far that they are solid formulations, and may be any ofpowders, granules, chewables, film coated tablets, sugar coated tabletsor the like, as well as tablets and capsules.

The mixture comprising the substance selected from the group consistingof 2,2-dichloro-12-(4-chlorophenyl)-dodecanoic acid, salts thereof, andesters thereof, and croscarmellose sodium may be either of the mixtureby the wet process or the dry process. For example, when the wet processis employed, the mixture may preferably be a kneaded mass which isobtained by uniform kneading after the addition of 10 to 40% by weightof a binding liquid such as water, ethanol, isopropanol or the like tothe aforementioned mixture. After the resulting kneaded mass is dried invacuum, the resulting product may be sized, if necessary, and then mixedwith magnesium stearate or the like to prepare tablets or capsules bythe above processes.

The pharmaceutical composition of the present invention manufactured asdescribed above is stable at a high temperature. For example, as for thetablets, a residual ratio of sodium2,2-dichloro-12-(4-chlorophenyl)-dodecanoate after a two-week storageunder a condition at 60° C. is not less than 90%, and as for thecapsules, a residual ratio of sodium2,2-dichloro-12-(4-chlorophenyl)-dodecanoate after one-week storageunder a condition at 60° C. is not less than 85%.

The pharmaceutical composition of the present invention is useful as amedicament for therapeutic treatment of diabetes-related diseases.Generally, the medicament may be administered once a day or severaltimes a day as divided portions normally in a daily dose of 1 to 600 mgas the weight of sodium 2,2-dichloro-12-(4-chlorophenyl)-dodecanoate.

EXAMPLES

The present invention will be explained more specifically with referenceto examples. However, the present invention is not limited to thefollowing examples.

Example 1

Sodium 2,2-dichloro-12-(4-chlorophenyl)-dodecanoate (10.0 g), lactose(1150.0 g), hydroxypropylcellulose (48.0 g), and croscarmellose sodium(120.0 g, tradename: Ac-Di-Sol, Asahi Kasei Co., Ltd.) were mixed for 10minutes by using planetary mixer (Shinagawa-shiki-kongo-kakuhan-ki;Dalton 5DML-03-R), and then the mixture was added with 400.0 ml ofpurified water and kneaded. Then, the resulting kneaded mass was driedin vacuum for 4 hours under a condition at 60° C., sized by cutting mill(Speed Mill), mixed with 12.0 g of magnesium stearate by using aV-blender, and compressed by using tablet press (Kikusui rotarycompressor 19TU) to obtain tablets (134.0 mg per tablet).

Example 2

Sodium 2,2-dichloro-12-(4-chlorophenyl)-dodecanoate (10.0 g), lactose(1058.0 g), and croscarmellose sodium (120.0 g, trade name: Ac-Di-Sol,Asahi Kasei Co., Ltd.) were mixed for 10 minutes by using a V-blender.The mixture was then added with 12.0 g of magnesium stearate and mixingwas further continued by using the V-blender. The mixture was compressedby using tablet press (Kikusui rotary compressor 19TU) to obtain tablets(120.0 mg per tablet).

Example 3 to Example 5

Tablets were prepared as 80.0 mg per tablet in a similar manner to thatof Example 2 with different contents of croscarmellose sodium.

Comparative Example 1

Tablets were prepared as 134.0 mg per tablet in a similar manner to thatof Example 1 by using low-substituted hydroxypropylcellulose, as also adisintegrant, instead of croscarmellose sodium.

Comparative Example 2

Tablets obtained in Comparative Example 1 were placed in glass bottles,and air in the bottles was substituted by nitrogen gas.

Comparative Example 3

Tablets were prepared as 134.0 mg per tablet in a similar manner to thatof comparative example 1 with further addition of corn starch.

Comparative Tests and Results

Each of the tablets obtained in Example 1 to 5 and Comparative Example 1to 3 was placed in a glass bottle, and each bottle was tightly sealedand stored for 2 weeks under the condition at 60° C. Each content ofsodium 2,2-dichloro-12-(4-chlorophenyl)-dodecanoate was determined byHPLC measurement after the 2-week storage. The results are shown inTable 1. TABLE 1 Compar- Compar- Compar- ative ative ative ExampleExample Example Example Example Example Example Example 1 2 3 4 5 1 2 3Sodium 2,2-dichloro-12-(4-chlorophenyl)-dodecanoate 1.0 1.0 5.0 5.0 5.01.0 1.0 1.0 Croscarmellose sodium 12.0 12.0 4.0 8.0 12.0 — — —Low-substituted hydroxypropylcellulose — — — — — 12.0 12.0 12.0 Cornstarch — — — — — — — 12.0 Lactose 115.0 105.8 70.2 66.2 62.2 115.0 115.0103.0 Hydroxypropylcellulose 4.8 — — — — 4.8 4.8 4.8 Magnesium stearate1.2 1.2 0.8 0.8 0.8 1.2 1.2 1.2 Total(mg) 134.0 120.0 80.0 80.0 80.0134.0 134.0 134.0 Residual ratio after storage at 60° C. for 2 weeks (%)93.7 93.9 96.3 97.2 97.8 84.9 88.3 87.8

Tablets of Comparative Example 1, where low-substitutedhydroxypropylcellulose was used as a disintegrant instead ofcroscarmellose sodium, gave poor stability of sodium2,2-dichloro-12-(4-chlorophenyl)-dodecanoate. Satisfactorily highstability was not achieved either by the storage under nitrogensubstitution by eliminating oxygen (Comparative Example 2), or by theadmixture of corn starch having moisture retaining property (ComparativeExample 3).

In contrast, each of tablets of Example 1 to 5, where croscarmellosesodium was mixed, sodium 2,2-dichloro-12-(4-chlorophenyl)-dodecanoatewas found to be stable after the storage for 2 weeks under a conditionat 60° C.

Example 6

Sodium 2,2-dichloro-12-(4-chlorophenyl)-dodecanoate (1.0 g), mannitol(211.5 g), talc (25.0 g), and croscarmellose sodium (12.5 g) were mixedby a V-blender for 10 minutes to obtain mixed powder. The resultingmixed powder (250.0 mg) was filled in HPMC capsule (size No.1) by usinga capsule filler to obtain a capsule.

Comparative Example 4

A capsule of 250.0 mg was prepared in a similar manner to that ofExample 6 except that croscarmellose sodium was not mixed.

Comparative Example 5

The capsule obtained in Comparative Example 4 was placed in a glassbottle and air in the bottle was substituted with nitrogen gas.

Comparative Example 6

A capsule of 250.0 mg was prepared in a similar manner to that ofExample 6 by using low-substituted hydroxypropylcellulose, as also adisintegrant, instead of croscarmellose sodium .

Comparative Example 7

A capsule of 250.0 mg was prepared in a similar manner to that ofExample 6 by using sodium carboxymethyl starch, as also a disintegrant,instead of croscarmellose sodium.

Comparative Tests and Results

With a similar manner to the above comparative tests for the tablets,residual amounts of sodium 2,2-dichloro-12-(4-chlorophenyl)-dodecanoatewere determined after storage of each of the capsules obtained inExample 6 and Comparative Examples 4 to 7 for a week under a conditionat 60° C. The results are shown in Table 2. TABLE 2 ComparativeComparative Comparative Comparative Example 6 Example 4 Example 5Example 6 Example 7 Sodium 2,2-dichloro-12-(4-chlorophenyl)-dodecanoate1.0 1.0 1.0 1.0 1.0 Mannitol 211.5 224.0 224.0 211.5 211.5 Talc 25.025.0 25.0 25.0 25.0 Croscarmellose sodium 12.5 — — — — Low substitutedhydroxypropylcellulose — — — 12.5 — Sodium carboxymethyl starch — — — —12.5 Total(mg) 250.0 250.0 250.0 250.0 250.0 Residual ratio afterstorage at 60° C. for 1 week (%) 88.5 70.1 73.5 67.7 57.6

Similar to the results of the tablets, the capsule of Example 6 mixedwith croscarmellose sodium was stable after the storage for one weekunder a condition at 60° C. compared with the other capsules ofcomparative examples.

INDUSTRIAL APPLICABILITY

The present invention provides a highly stable pharmaceuticalcomposition comprising 2,2-dichloro-12-(4-chlorophenyl)-dodecanoic acid.

1. A pharmaceutical composition which comprises a mixture comprising: asubstance selected from the group consisting of 2,2-dichloro-12-(4-chlorophenyl)-dodecanoic acid, a salt thereof, and an esterthereof, and croscarmellose sodium.
 2. The pharmaceutical compositionaccording to claim 1 in which a mixing ratio of the substance selectedfrom the group consisting of 2,2-dichloro-12-(4-chlorophenyl)-dodecanoicacid, the salt thereof, and the ester thereof, and the croscarmellosesodium is from 10:1 to 1:20.
 3. A stabilizer for a substance selectedfrom the group consisting of 2,2-dichloro-12-(4-chlorophenyl)-dodecanoicacid, a salt thereof, and an ester thereof, which comprisescroscarmellose sodium.
 4. A method for stabilization of a substanceselected from the group consisting of2,2-dichloro-12-(4-chlorophenyl)-dodecanoic acid, a salt thereof, and anester thereof, which comprises the step of preparing a mixturecomprising the substance selected from the group consisting of2,2-dichloro- 12-(4-chlorophenyl)-dodecanoic acid, the salt thereof, andthe ester thereof, and croscarmellose sodium.